1. Field of the Invention
The invention relates to composition and methods for the treatment of cancer, and in particular for protocols for combination chemotherapy. More specifically, the patent application deals with protocols that combine growth factor receptor inhibitors (also referred to as receptor blockers or growth factor blockers) with phase specific cell cycle active cytotoxic chemotherapeutics.
A big part of the problem with prior art protocols that use growth factor receptor inhibitors in combination with phase specific cell cycle active cytotoxic chemotherapeutics is that prior art practitioners do not even realize there is a problem. Receptor inhibitors are used concurrently with phase specific cytotoxics, as stipulated in their full prescribing information, and these protocols are summarized in the specification section of this application. Applicant will show why this is a problem. In summary, the prior art protocols result in antagonistic function, wherein only the first administration of phase specific cytotoxic chemotherapy works, and all subsequent administrations result only in systemic toxicity with no therapeutic benefit. Doing harm (systemic toxicity), without therapeutic benefit, is a violation of medical ethics. Accordingly, a compelling case can be made that the major receptor inhibitor manufacturers (e.g. Genentech, ImClone/Bristol Myers, AstraZeneca, etc. . . . ) are not aware of the problem.
Applicant will outline the mechanisms of action related to why prior art protocols have a problem. Applicant will also provide clinical corroboration of the problem, including using Genentech's own Phase III human data. Applicant will then propose novel protocols that result in synergistic function, whereby a much better treatment method will by provided.
2. Description of Related Art
The curative value of chemotherapy as used under prior art is minimal at best. Advanced stage cancers, which rely primarily on chemotherapy for a cure, indicate just how modest chemotherapy's contribution is under prior art: the 5 year survival rate for Stage 1V metastatic lung cancer is 1%, Stage 1V metastatic colon cancer is 5%, pancreatic cancer is 2%, and Stage 1V metastatic breast cancer is 14% (Harrison's 15th ed. pgs. 565, 584, 591, 575 respectively). Prior art chemotherapy only extends median survival by a few months of misery.
There are around 50 chemotherapeutic agents available for use today. Most of them are cell cycle active cytotoxic, meaning they kill actively proliferating cells. Most of these chemotherapeutics are cytotoxic during a given phase of the cell cycle (i.e. phase specific). Of the chemotherapeutics listed in Harrison's Principles of Internal Medicine, 15th. edition, pgs. 538-541, roughly 60% are S-Phase specific and 14% are M-Phase specific.
A brief review of currently used chemotherapeutics is presented for reference.
Topoisomerase inhibitors induce cytotoxicity by interfering with the enzymes topoisomerase 1 and topoisomerase 2. DNA replication results in torsional strain that, if not relieved by topoisomerase, results in DNA strand breakage. Topoisomerase 1 inhibitors include irinotecan, topotecan, and camptothecin. Topoisomerase 2 inhibitors include epipodophyllotoxins such as etoposide and teniposide and anthracyclines such as daunorubicin, doxorubicin, and idarubicin. Topoisomerase inhibitors are S-Phase specific.
Antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. Pyrimidine analogs include cytarabine, fluorouracil (5 FU), and gemcitabine. Purine analogs include cladribine, fludarabine, and pentostatin. Other antimetabolites include hydroxyurea and methotrexate. They are S-Phase specific.
Alkylating agents are efficient at cross-linking DNA, leading to strand breakage. Alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine (nitrogen mustard), chlorambucil, thiotepa, carmustine, lomustine as well as platinum compounds such as cisplatin and carboplatin, which are not true alkylating agents also lead to covalent cross linking of DNA. These agents are classified as non-phase specific.
Plant Alkaloids include vincristine, vinblastine, and vinorelbine which inhibit microtubule assembly by binding to tubulin and docetaxel and paclitaxel which function by stabilizing microtubules and preventing their disassembly. They are cell cycle active and cytotoxic predominately during the M phase of the cell cycle.
Bleomycin induces DNA strand breakage through free radical generation and is cytotoxic mainly during the G2 and M phase. Mitomycin C cross links DNA.
Other Agents include dacarbazine and procarbazine which act as alkylating agents to damage DNA and L-Asparaginase, the only enzyme used as a anti tumor agent, which acts by depletion of extracellular pools of asparagine.
Imatinib (Gleevec from Novartis) functions as an inhibitor of a number of tyrosine kinase enzymes by binding to the kinase domain.
Growth Factor Receptor Inhibitors (receptor blockers) target specific growth factor receptors and prevent their activation. Commercially available receptor blockers include receptor monoclonal antibodies (MAbs) and small molecule receptor inhibitors. MAb receptor inhibitors commercially available are Trastuzumab (Genentech's Herceptin) which is a HER2 antibody and cetuximab (ImClone's Erbitux) and panitumumab (Amgen's Vectibix) which are a HER1 (EGFR) antibodies. Small molecule receptor inhibitors commercially available include gefitinib (AstraZeneca's Iressa) and erlotinib (Genentech's tarceva), both of which are HER1 blockers.
Angiogenesis Inhibitors do not directly target the cancer cells but function indirectly by inhibiting blood vessel (endothelial cell) growth in tumors and include drugs such as Bevacizumab (Genentech's Avastin®) which is a antibody that binds to VEGF and numerous other angiogenesis inhibitors are currently in clinical trials.
Protocols for administering cell cycle active chemotherapy were developed, in many cases, decades ago under concepts of “maximum tolerated doses” which were primarily designed to allow for recovery from systemic toxicity. Traditional “legacy protocols” administer a dose of chemotherapy every 7 or 21 days for several cycles. Higher frequency protocols administer chemotherapy at lower doses every day for 3-5 days for several cycles or at ultra low doses every day for up to 21 days (Harrison's Principles of Internal Medicine, 15th. edition, pgs. 538-541).
Angiogenesis inhibitors are administered continually over the course of a chemotherapeutic regimen and they have been able to further extend median survival by 2 to 5 months, depending on cancer type (per Genentech's Avastin full prescribing information).
Growth factor receptor blockers have come on the scene over the last several years. They are administered either as a single agent treatment option or are administered concurrently with conventional chemotherapeutic regimens. The combination receptor blocker/conventional chemotherapy protocols are the topic of present invention.